Phenothiazine tranquilizers undergo extensive biotransformation in the body. One of the metabolites, 7,8-dihydroxychlorpromazine, has been recently identified in patients receiving chlorpromazine, and shown to be pharmacologically active. In vitro, it inhibits Na-K-ATPase and releases calcium from mitochondria. These compounds (dihydroxyphenothiazine metabolites) produce a positive inotropic action in the isolated heart. Pharmacologic properties of chemically related phenothiazine metabolites will be studied in left atrial and Langendorff preparations of guinea pig hearts and in open-chest anesthetized dogs. In order to elucidate the molecular mechanisms of these actions, effects of these agents on Na-K-ATPase, and the partial reactions associated with this enzyme activity, will be studied using crude enzyme preparation obtained from guinea pig heart and partially purified enzyme preparations obtained from rat brain. Interactions of these agents with the cardiac glycosides will also be studied. It is expected that an interesting compound with positive inotropic properties will be uncovered and that an insight into the mechanisms by which drugs alter cardiac functions may be obtained. Additionally, the molecular mechanisms for cardiac toxicity of phenothiazine tranquilizers may be elucidated.